New retron-based DNA editing method to replace CRISPR offers hope for broad treatment of complex genetic diseases

Researchers at the University of Texas at Austin have developed a gene editing technique that can replace damaged DNA segments in their entirety, simultaneously correct a variety of rare mutations, and achieve an efficiency of about 30% of target cells – with initial applications in cystic fibrosis and scoliosis.

Researchers at the University of Texas at Austin have developed a particularly efficient gene editing method that is capable of correcting a wide variety of DNA mutations in a single step in a large number of body cells.

This breakthrough could revolutionize genetic medicine, as it promises to make treatments for complex diseases faster, more effective, and relevant to much larger groups of patients.

The obstacle: complex genetic diseases with countless mutations

Some genetic diseases – including cystic fibrosis (CF), hemophilia and Tay-Sachs disease – are caused not by a single mutation, but by several different mutations scattered throughout the genome. The number and type of mutations can vary greatly even among patients diagnosed with the same disease. This variability makes it very difficult to develop gene therapies that are suitable for large groups of patients, rather than targeted solutions that are only intended for carriers of one or two specific mutations.

Now, researchers at The University of Texas at Austin have introduced an improved gene-editing technique that offers greater precision and efficiency than previous methods. The method can simultaneously correct a large number of disease-related mutations in mammalian cells. The team also used it to successfully correct mutations associated with scoliosis in zebrafish embryos.

The core of the new method is based on retrons – genetic components found in bacteria that contribute to their defense against viral infections. This is the first time that scientists have used retrons to correct a disease-causing mutation in vertebrates, opening the door to developing new gene therapies in humans as well.

A broader and more inclusive strategy for gene editing

“Many gene-editing techniques currently available are limited to one or two mutations, which leaves a lot of people out of the picture,” says Jesse Buffington, a doctoral student at the university and one of the authors of the new paper published in Nature Biotechnology. “My hope, and what drives me, is to develop a gene-editing technology that is much better at capturing people with more unique disease-causing mutations—and that with retrons we can extend that impact to a much broader patient population.”

Buffington led the study with Professor Ilya Finkelstein, of the Department of Molecular Biology at the University of Texas. The research was supported by Retronix Bio and the Welch Foundation.

Replacing a damaged DNA segment in one step
The new retron-based method is capable of replacing a long segment of damaged DNA with a normal version of that segment. Because the method repairs an entire segment rather than focusing on a single mutation at a time, the same “retron packaging” can repair a wide range of different mutations found within the same region – without the need to tailor a separate solution to each patient’s unique genetic sequence.

“We want to democratize gene therapy by creating off-the-shelf tools that can cure large groups of patients in one go,” says Finkelstein. “This should make developing treatments much more economically viable, and also significantly simplify the regulatory side – because only one FDA approval is required for one tool.”

Dramatic improvement in editing efficiency
Previous attempts to use retrotrans to edit genes in mammalian cells have had very limited success: the best systems have managed to incorporate new DNA into only about 1.5% of the target cells. The University of Texas method has seen a dramatic improvement, with success in about 30% of the target cells. The researchers believe they have the potential to increase efficiency even further as the system undergoes further improvements.

Another advantage is that the retrotrans system can be delivered as RNA packaged within lipid nanoparticles. These particles are specifically designed to overcome delivery problems that limit many standard gene editing tools.

Targeting cystic fibrosis

Researchers are now applying the method to treat cystic fibrosis (CF), a disease caused by mutations in the CFTR gene. These mutations cause thick mucus to build up in the lungs, chronic infections, and the gradual destruction of lung tissue. A research grant from Emily's Entourage, a nonprofit focused on the 10 percent of CF patients who do not respond to existing treatments, will help advance this research.

The team has already begun replacing defective regions of the CFTR gene in disease-supporting cell culture models that simulate the disease process. The next step is to move on to airway cells derived directly from CF patients.

Expanding treatment options for rare mutations

“Traditional gene editing technologies work best against a single mutation, and they are very expensive to adapt,” says Buffington. “That’s why many gene therapies focus on the most common mutations. But there are more than a thousand different mutations that can cause CF. It’s simply not economically viable for companies to develop a gene therapy for, say, just three people. With our retrotransposon-based approach, we can ‘cut out’ the entire defective region and replace it with a normal version—and thus affect a much larger portion of the CF patient population.”

Another grant from the Cystic Fibrosis Foundation will support similar research on another region of the CFTR gene, which contains the most common disease-causing mutations.

for the scientific articlehttps://www.nature.com/articles/s41587-025-02879-3